Desenvolvimento de Mn-Porfirinas à base de N-alquilpiridilporfirinas e N-alquilquinolilporfirinas como candidatos a agentes terapêuticos redox-ativos

Abstract

Water-soluble cationic Mn(III) porphyrins derived from 2-N-pyridylporphyrins were originally developed as potent mimics of superoxide dismutase (SOD) enzymes, catalysts of peroxynitrite decomposition, and later proved to be efficient redox-active therapeutic agents. In this thesis, three independent studies were developed, focusing on Mn-Porphyrins based on N-alkylpyridylporphyrins and N-alkylquinolylporphyrins. Initially, the first study was carried out on the kinetics of thermal degradation (under isothermal and non-isothermal conditions) of a redox-active MnP, MnTE-2-PyPCl5, being the compound of choice in most exploratory preclinical studies, for having an established reputation for the design of bioavailable SOD mimics. In this study, a multilayer neural network (MLP) allowed the simultaneous evaluation of ten kinetic models; activation energy values calculated from isothermal and non-isothermal data agree with each other and are consistent with the high thermal stability of MnTE-2-PyPCl5 observed in the solid state. The t90% shelf-life value at 25 °C, estimated from the isothermal decomposition data, was approximately 17 years. Additionally, a spectrophotometric protocol was developed to determine the molar absorptivity of MnTE-2-PyPCl5 using thermogravimetric analysis (TG) and differential thermal analysis (DTA) as a tool. The conditions for the determination of molar absorptivity from the thermal analysis dehydration step were established. Finally, the last study concerns the attempt to develop a new class of porphyrins containing the 2-quinoline group. Some difficulties were encountered during its execution: among them, the non-reproducibility of the syntheses, which was related to the quality of the commercial 2-quinolinecarboxaldehyde. Despite the difficulties, synthetic routes were developed to obtain H2T-2-QnP, H2TM-2-QnP4+ and MnTM-2-QnP5+. The compounds were isolated in 5, 68 and 78 % yields, respectively.